The fundamental structural units of peptides are .alpha.-amino acids, about 20 of which are the building units for all proteins. All amino acids except the simplest one, glycine, are capable of existing in both D and L configurations with respect to their .alpha.-carbon, but naturally occurring proteins contain only the L-enantiomers. Peptides are dimers, oligomers, or long-chain polymers (polypeptides) which formally result from the condensation of the amino acids to thus produce amide (commonly called peptide or peptidyl) linkages, --CONH--.
Hydrolysis of proteins and peptides has been studied more from the biochemical than from the chemical point of view, but the mechanisms at the molecular level of these important reactions remain largely obscure. As reported by D. Kahne et al., J. Amer. Chem. Soc., 110, 7529 (1988), the half-life for hydrolysis of the amide bond in neutral aqueous solution is about 7 years. Even with the strongest acids or bases in high concentrations, prolonged heating is necessary. Because of this extreme unreactivity, kinetic and mechanistic studies have been done almost exclusively with amides that are variously activated by substituents, by ring strain, by forced nonplanarity, or by proximate functional groups. For example, see R. Kluger et al., J. Amer. Chem. Soc., 111, 5921 (1989); ibid., 101., 6976 (1979). Moreover, the reaction mixtures usually are heated to promote cleavage.
However, proteolytic enzymes, such as chymotrypsin, hydrolyze even unactivated amide bonds rapidly under mild conditions. For example, see A. Fersht, Enzyme Structure and Mechanism, Freeman, N.Y. (2d ed. 1985) at pages 405-425. Although some biomimetic systems surpass chymotrypsin in the rate of stoichiometric hydrolysis of activated esters, these systems fall short of enzymes, which are true catalysts and which hydrolyze even unactivated amides. See, F. M. Menger et al., J. Amer. Chem. Soc., 109, 3145 (1987). Catalytic antibodies hold promise for enzyme-like hydrolysis of peptides because these agents are true catalysts and because they show selectivity. For example, see S. Benkovic et al., Science, 2.50, 1135 (1990).
Since certain proteolytic enzymes are known to require metal ions for activity, ester hydrolysis has been attempted using various metal complexes. However, carboxylic and phosphate esters are used as substrates more often than amides. For example, see R. W. Hay et al., in Metal Ions in Biological Systems, Vol. 5, H. Sigel, ed., Marcel Dekker, N.Y. (1976) at page 173 and D. P. N. Satchell et al., Annu. Rev. Prog. Chem., Sect. A: Phys. Inorq. Chem., 75, 25 (1978). Complexes of cobalt(III) and of copper(II) have been studied more than any other, and mechanisms by which these metal ions act are known in detail. See, P. A. Sutton et al., Acc. Chem. Rec., 20, 357 (1987) (Co(III)) and J. Chin, Acc. Chem. Res., 24, 145 (1991) (Co(III) and Cu(II)). Since cobalt(III) complexes bind to the N-terminal amino-acid residue of peptides, only the N-terminal amide bond in the peptide is hydrolyzed. Although these reactions are stoichiometric, they are relevant to turnover reactions catalyzed by aminopeptidases. Recent reports of oxidative cleavage of proteins mediated by metal complexes widen the range of inorganic methodologies for accomplishing these biochemical reactions. For example, see T. M. Rana et al., J. Amer. Chem. Soc., 112, 2457 (1990), ibid., 113, 1859 (1990); T. M. Rana et al., PNAS USA, 88, 10578 (1991).
Platinum(II) complexes have been used previously to promote hydrolysis of inorganic oligophosphates and of activated phosphate esters. For example, see R. N. Bose et al., Inorg. Chem., 24, 3989 (1985) and M. A. De Rosch et al., Inorg. Chem., 29, 2409 (1990). However, a continuing need exists for methods to selectively hydrolyze peptide bonds under mild conditions.